Goorha Flashcards
1
Q
What symptoms are common with pancytopenia?
A
- Fever
- Mouth sores
- Shortness of breath
2
Q
What is the most common etiology of aplastic anemia?
A
Idiopathic
3
Q
What are the mechanisms that cause pancytopenia?
A
- Bone marrow failure
- Destruction of blood cells in the peripheral blood
4
Q
What is bone marrow failure?
A
- Pancytopenia due to the failure of bone marrow to produce blood cells -> includes low RBCs (anemia), WBCs (leukopenia), and platelets
1. Symptoms of anemia: difficulty breathing, chest pain, fatigue
2. Symptoms of leukopenia/neutropenia: fever, infection, mouth sores
3. Symptom of thrombocytopenia: bleeding
5
Q
What is the differential diagnosis of pancytopenia?
A
- Increased destruction: immune destruction, sepsis, hypersplenism
- Decreased production: myelodysplasia, marrow infiltrate, B12 deficiency, aplastic anemia, drugs, viruses, radiation
6
Q
What are some typical causes bone marrow failure via hypo- and hypercellular bone marrow?
A
- Hypocellular: aplastic anemia
1. Congenital: Fanconi
2. Acquired: ideopathic, myelodysplastic syn (more often hypercellular), drugs/chemicals, radiation, viruses - Hypercellular: bone marrow infiltration
1. Hematologic malignancies, carcinoma, storage disorders, myelodysplastic syndromes, B12 or folate deficiency
7
Q
What is aplastic anemia?
A
- Severe, life-threatening syndrome in which production of erythrocytes, ABCs, and PLT has failed
- May occur in all age groups, both genders
- Characterized by peripheral pancytopenia, and accompanied by hypocellular bone marrow
8
Q
What is a primary mechanism of idiopathic aplastic anemia?
A
- Immune-mediated destruction of hematopoietic stem cells
9
Q
What is the pathophysiology of aplastic anemia?
A
- Primary defect is reduction in, or depletion of hematopoietic precursor stem cells with decreased production in all cell lines -> leads to PERIPHERAL PANCYTOPENIA
1. May be due to quant/qualitative damage to pluripotent stem cell
2. Result of defective bone marrow microenvo
3. Form of cellular/humoral immunosuppression of hematopoiesis
10
Q
What are the 2 congenital disorders associated with aplastic anemia?
A
-
Fanconi’s anemia: chromosomal instability syndrome
1. Disorder usually becomes symptomatic at about 5 y/o and is associated with progressive bone marrow hypoplasia
2. Congenital defects like small stature and skin hyperpigmentation also seen in affected ppl - Familial aplastic anemia: subset of Fanconi’s in which congenital defects absent (can even present at later age, including in adulthood)
11
Q
What are treatment options for aplastic anemia?
A
- Immunosuppression
- Stem cell transplant
- Transfusion
12
Q
What are the acquired causes of aplastic anemia?
A
- Most common is idiopathic: no hx of exposures to substances known to be causative agents of disease
- Ionizing radiation: hematopoietic cells particularly susceptible to destruction (300-500 rads can wipe it out, but recovery with sublethal doses)
- Chemical agents: incl. those with benzene ring, chemo, and certain insecticides
- Idiosyncratic rxns to some drugs: like quinacrine or chloramphenicol (not commonly used anymore)
- Infections: viral/bac like mono, hepatitis, parvovirus, CMV, and miliary TB
- Pregnancy: rare
- PNH: stem cell disease (PIG-A) in which membranes of RBCs, WBCs, & PLTs have abnormality making them susceptible to complement-mediated lysis
13
Q
What lab findings are associated with aplastic anemia?
A
- Severe pancytopenia with relative lymphocytosis (b/c they live a long time)
- Normochromic, normocytic RBCs (may be slightly macrocytic)
- Mild to moderate anisocytosis, poikilocytosis
- Decreased reticulocyte count (HALLMARK FINDING)
- Hypocellular bone marrow with >70% yellow marrow (predominantly fat)
14
Q
What is the tx for aplastic anemia?
A
- Should include:
1. Withdrawal of potentially offending agents
2. Supportive care (e.g., transfusion, ABs)
3. Immunosuppressive regimens: anti-thymocyte globulin, cyclosporine, steroids often effective at improving counts -> suggests auto-immune destruction of hematopoietic stem cells a primary cause of idiopathic aplastic anemia
4. Hematopoietic stem cell transplantation - If there is a problem, look at the drugs your pt is on first (to see if they are causing the aplastic anemia)
15
Q
What is pure red cell aplasia?
A
- Characterized by a selective decrease in erythroid precursor cells in bone marrow -> WBCs, platelets unaffected
-
Acquired:
1. Transitory with viral/bac infections
2. Pts w/hemolytic anemias may suddenly halt erythropoiesis
3. Pts w/thymoma: T-cell mediated responses against bone marrow erythroblasts or EPO sometimes produced (potential TEST QUESTION) - Treatment: supportive care and immunosuppression
16
Q
What is the primary difference between myelodysplastic syndrome and aplastic anemia?
A
- Presence or absence of neoplastic cells in the bone marrow
17
Q
In brief, what are MDS? What will you see in the bone marrow and peripheral smear?
A
-
Myelodysplastic syndromes: primary, neoplastic stem cell disorders that tend to terminate in acute leukemia
1. Bone marrow: normocellular, or hypercellular usually w/evidence of QUAL abnormalities in 1 or more cell lines -> ineffective erythropoiesis, granulopoiesis, and/or megakaryopoiesis
a. Ringed sideroblasts, o/dysplastic changes
2. Peripheral smear: dysplastic cells, including nucleated RBCs, oval macrocytes, pseudo-_Pelger-Huet PMNs_ (HYPO-segmented polys) w/hyper-chromatin clumping, hypo-granulated neutrophils, and giant bizarre platelets
18
Q
What do you see here? What is this characteristic of?
A
- Pelger-Huet poly
- Commonly seen in MDS
- NOTE: there is also a congenital anomaly that causes abnormal segmentation of polys and no other side effects -> these people might be erroneously treated for infection due to “apparent left shift”
19
Q
What are these? When might you see them?
A
- Ringed sideroblasts
- Commonly seen with MDS
20
Q
What is the pathogenesis of MDS?
A
- Thought to arise from mutations in multi-potent bone marrow stem cell, but specific defects responsible for these diseases remain poorly understood
1. Differentiation of blood precursor cells impaired, and significant INC in levels of apoptotic cell death in marrow cells
2. Clonal expansion of abnormal cells causes production of cells with lost ability to differentiate (presence of a neoplastic clone differentiates from aplastic anemia) - If overall % of bone marrow blasts rises above 20% for WHO, 30% for FAB, then transformation to AML said to have occurred
21
Q
What percentage of untreated MDS patients will develop AML?
A
90-95%
22
Q
What is the treatment for MDS?
A
- Goals of therapy: to control symptoms, improve QOL, improve overall survival, and DEC progression to AML
- Supportive therapy w/blood product support and hematopoietic growth factors (i.e., EPO)
- Chemo w/hypo-methylating agents 5-azacytidine and decitabine (< toxic than older drugs; not entirely sure how they work, but may have to do w/de-methylation to allow differentiation) decreases blood transfusion requirements, slows progression to AML, INC survival
- Lenalidomide (5q), HSCT
23
Q
What is lenalidomide? What is it used to treat?
A
- Approved in Dec, 2005 only for use in 5q syndrome (subset of MDS)
- Multiple MOA: in vitro -> direct anti-tumor effect, inhibition of angiogenesis, and immunomodulatory role; in vivo -> induces tumor cell apoptosis directly, indirectly via inhibition of bone marrow stromal cell support, anti-angiogenic and anti-osteoclastogenic effects, and immunomodulatory activity
- Broad range of activities that can be exploited to treat many hematologic and solid cancers
24
Q
When is HSCT used to treat MDS? Why?
A
- Hematopoetic Stem cell transplantation
- In younger patients (<60 y/o), and more severely affected patients
- Offers the potential for curative therapy
- Has grown immensely in past several years
25
What are the different kinds of stem cell transplantation?
- BMT: bone marrow transplant
- HSCT: hematopoietic stem cell transplant
1. Transplantation of hematopoietic progenitor cells that have the ability to _proliferate and repopulate the marrow spaces_
- PBCST: peripheral blood stem cell transplant
26
What is autologous HSCT?
- Use of stem cells collected from pt, stored in freezer to be reinfused, transplanted at later date
- Because infused stem cells belong to recipient, there is _minimal_ to no risk of rxn b/t cells and donor -\> the _overall risk of morbidity/mortality from auto SCT low_
- Allows use of high-dose chemo in pt – dose that would normally wipe out hematopoetic stem cells -\> _stored stem cells rescue the pt’s hematopoetic system after chemo_ (RESCUE THERAPY)
- Mainly in tx of LYMPHOMAS, MULTIPLE MYELOMA
27
What is allogeneic HSCT?
- Related or unrelated HLA (human leukocyte antigen) matched donors as source of stem cells -\> matching is based on variability at _3 or more loci of HLA gene_, and perfect match at these loci preferred to prevent GVHD
1. Mech not clearly understood, but _transplanted cells selectively recognize tumor cells_ (and don't attack the recipient’s body)
- Even if good match at critical alleles, GVHD can still occur, and the recipient will need immunosuppressive meds. Incidence of **GVHD** significantly increases risk of morbidity and mortality in pts who do allogeneic SCT vs autologous stem cell transplant
28
What are the advantages of allogeneic SCT compared to autologous?
- _Can be used when recipient/pt’s bone marrow fails_, i.e., if they have aplastic anemia or MDS
- When recipient has certain diseases (i.e., leukemia or lymphoma), donor cells can attack these tumor cells via graft versus disease effect to prevent relapse of the tumor -\> _used to prevent relapse of tumor and ultimately cure the patient _
29
Know this.
Good job!
30
Case: 18 y/o AAM with fatigue and passing out. Wbc = 0.8, hgb = 5.5, platelets = 40,000. No family hx of blood problems. Exam unremarkable. Reticulocyte count \< 2%. Bone marrow biopsy showed hypocellular marrow w/\<10% cellularity. Dx: severe aplastic amemia.
Tx w/anti-thymocyte globulin (immunosuppressant rabbit or horse Abs for T-cells; also used for organ transplant), steroids, and cyclosporine. Blood counts did not improve. Required blood and PLT transfusion 1-2 times/week. No infectious complications, however. _What is next step in patient's treatment? _
- **HLA typing of patient's siblings**
- He then underwent allogeneic stem cell transplantaion. The donor was his fraternal twin brother
- Currently, he is 4 years after transplant. He is off of all medications (including immunosuppressive therapy), and is attending college
- Blood counts are normal
31
What are the symptoms of GVHD? How might you resolve it?
- Skin (can get really bad, with patients having to be treated like burn patients), gut (can be severe -\> dehydration), liver (can even cause liver failure in extreme cases), eyes.
- To resolve this, now immunotherapy w/engineering of T and B-cells targeted specifically at tumor (new drug targeted for CD19 - ALL and CLL). **5-AZA** _is the example Dr. Strom talked about (prevention of methylation by inserting cytidine with N atom at C-5)_
1. According to Google, INC #'s of host CD8+ and Tregs
32
What is not a common symptom of acute leukemia?
Hearing loss
33
What are 4 common symptoms of acute leukemia?
- Fever
- Nose bleed
- Fatigue
- Rash
34
Can AML and ALL be easily differentiated via review of the peripheral smear?
- No
- Main distinguishing feature is the Auer rod, but you will frequently not see these
- Bone marrow or peripheral blood flow cytometry needed to distinguish these
35
What tests are important in diagnosing and treating acute leukemias?
- Bone marrow biopsy
- Flow cytometry
- Cytogenetics
- Molecular analysis
36
What are the leukemias?
- Group of heterogenous disorders characterized by _accumulation of malignant white cells in bone marrow and blood_
- Abnormal cells cause morbidity/mortality due to:
1. _Bone marrow failure_: anemia, neutropenia, thrombocytopenia
2. _Infiltration of organs_: liver, spleen, lymph nodes, meninges, brain, skin or testes
37
What are the major causes of AML?
- Chemo (as people are living longer, this problem or tx-related leukemia is becoming more common)
- Pre-existing hematologic disorder, like MDS
38
What is the incidence of ALL vs. AML?
- **ALL**: most comm form of leukemia in children (what St. Jude is known for); incidence _highest 3-7 y/o_, falls off by 10, then secondary rise by age 40
- **AML**: all age groups; most comm form of acute leukemia in adults, and _increasingly common with age_, i.e., an age-related malignancy
1. Important distinction b/t primary AML (de novo) and secondary AML (develops from MDS or other hematologic malignancies) -\> _Secondary AML is more difficult to treat_
39
Is smoking associated with devo of AML?
No
40
What are the most useful immunological markers for AML/ALL diagnosis?
- Myeloid antigens include: MPO, CD33, CD13, HLA-DR
- Lymphoid antigens include: TdT, CD10, CD19, CD20
